Promotion of rat hepatocarcinogenesis by dimethylarsinic acid: association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver.
Arsenicals are epidemiologically significant chemicals in relation to induction of liver cancer in man. In the present study, we investigated the dose-dependent promotion potential of dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenicals in mammals, in a rat liver carcinogenesis model. In experiment 1, glutathione-S-transferase placental form (GST-P)-positive foci, putative preneoplastic lesions, were employed as endpoints of a liver medium-term bioassay for carcinogens (Ito test). Starting 2 weeks after initiation with diethylnitrosamine, male F344 rats were treated with 0, 25, 50 or 100 ppm of DMAA in the drinking water for 6 weeks. All animals underwent two-thirds partial hepatectomy at week 3 after initiation. Examination of liver sections after termination at 8 weeks revealed dose-dependent increases in the numbers and areas of GST-P-positive foci in DMAA-treated rats as compared with controls. In experiment 2, ornithine decarboxylase activity, which is a biomarker of cell proliferation, was found to be significantly increased in the livers of rats treated with DMAA. In experiment 3, formation of 8-hydroxydeoxyguanosine, which is a marker of oxygen radical-mediated DNA damage, was significantly increased after administration of DMAA. These results indicate that DMAA has the potential to promote rat liver carcinogenesis, possibly via a mechanism involving stimulation of cell proliferation and DNA damage caused by oxygen radicals.
Wanibuchi
H
H
First Department of Pathology, Osaka City University Medical School.
Hori
T
T
Meenakshi
V
V
Ichihara
T
T
Yamamoto
S
S
Yano
Y
Y
Otani
S
S
Nakae
D
D
Konishi
Y
Y
Fukushima
S
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002101:Cacodylic Acid / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006540:Herbicides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D006540:Herbicides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D002101:Cacodylic Acid; D009955:Ornithine Decarboxylase; D003849:Deoxyguanosine